bcr is gene which exists in the human twenty-second chromosome and abl is gene which exists in the human ninth chromosome, and Philadelphia chromosome is formed by translocation of the human twenty-second and ninth chromosomes. It is known that a gene product of the chromosome, BCR-ABL, is protein having tyrosine kinase activity and constantly generates the growth signal to cause aberrant growth of cells (see, for example, Non-Patent Document 2).
Therefore, inhibition of the BCR-ABL tyrosine kinase activity makes it possible to suppress cell growth caused by the kinase and a compound which inhibits the activity is suited for use as a therapeutic agent for diseases such as chronic myelogenous leukemia, acute lymphoblastic leukemia and acute myelogenous leukemia. Although Glivec® (see, for example, Patent Document 1) has already been put on the market as a drug having the same action, other drugs having the same action mechanism have never been put on the market and thus it has been required to develop more excellent medicines.
It has recently been reported that recurrence is often recognized in patients wherein remission is attained by administration of Glivec® in BCR-ABL-positive acute lymphoblastic leukemia, in addition to examples of blastic crisis of chronic myelogenous leukemia (see, for example, Non-Patent Document 3). As a result of examination of leukemia cells of the patients suffering from the recurrence of disease, the appearance of a variant such as E255K is recognized (see, for example, Non-Patent Documents 4 to 7). Also in examples of administration of Glivec® to the patients with BCR-ABL-positive acute lymphoblastic leukemia, the appearance of resistant cells which mainly exhibits variation of E255K is recognized (see, for example, Non-Patent Document 8). With an increase in use of Glivec®, resistant patients further increase and thus it is required to develop a therapy.
Patent Document 1:
Japanese Unexamined Patent No. 6-87834
Patent Document 2:
Pamphlet of International Publication WO 02/22597
Non-Patent Document 1:
Shtivelman E, et al.: Nature, 1985, 315, 550-554
Non-Patent Document 2:
Daley G Q, et al.: Science, 1990, 247, 824-830
Non-Patent Document 3:
Druker B J, et al.: N Engl J Med, 2001, 344, 1038-1042
Non-Patent Document 4:
Weisberg E, et al.: Drug Resist Updat, 2001, 4, 22-28
Non-Patent Document 5:
Gorre M E, et al.: Science, 2001, 293, 876-880
Non-Patent Document 6:
Blagosklonny M V: Leukemia, 2002, 16, 570-572
Non-Patent Document 7:
Hochhaus A, et al.: Leukemia, 2002, 16, 2190-2196
Non-Patent Document 8:
Hofmann W-K, et al.: blood, 2002, 99, 1860-1862
Non-Patent Document 9:
Deninger W N, et al.: blood, 2000, 96, 3343-3356
Non-Patent Document 10:
J. Org. Chem., 1996, 61, 1133-1135
Non-Patent Document 11:
J. Org. Chem., 2000, 65, 1144-1157
Non-Patent Document 12:
Recl. Trav. Chim. Pays-Bas., 1950, 69, 673-699
Non-Patent Document 13:
J. Med. Chem., 2000, 43, 1508-1518
Non-Patent Document 14:
J. Med. Chem., 1975, 18, 1077-1088
Non-Patent Document 15:
Bioorg. Med. Chem. Lett., 2001, 11, 2235-2239
Non-Patent Document 16:
J. Heterocyclic Chem., 2000, 37, 1457-1462
Non-Patent Document 17:
J. Med. Chem., 2000, 43(8), 1508-1518
Non-Patent Document 18:
Khim. Geterotsikl. Soedim., 1981, (7), 958-962
Non-Patent Document 19:
J. Heterocyclic Chem., 1990, 27, 579-582
Non-Patent Document 20:
Arzneim.-Forsch./Drug Res., 1989, 39(2), 1196-1201
Non-Patent Document 21:
J. Org. Chem., 1996, 61, 7240-7241